Pharmaceutical are the most commonly employed method to deliver drug substances. However, a difficulty in the formulation and preparation of relatively low dose active pharmaceutical ingredients is content uniformity. At low dosages, relatively good content uniformity of a mixture of one API (targeted for relatively low dosage) and one API (targeted for a relatively higher relative dosage) is challenging. Similarly, at low dosages, relatively good content uniformity of a mixture of one API (targeted for relatively low dosage) with an excipient (present at a relatively high level), is again difficult to achieve in connection of assuring reliable drug uniformity.
For example, when two APIs are to be delivered in suspension, where one is targeted at a relatively low dosage, and one is targeted for a relatively high dosage, separate milling of the solid APIs, and then combination of the two APIs, typically leads to difficulty in measurement and non-uniformity in suspension content, thereby raising concerns that dosage targets have been compromised.
In fact, it is particularly challenging to deliver a relatively low dose medicine from a suspension dosage when dealing with relatively small volume (as low as 0.1 mL) of a relatively low concentration formulation (e.g., 0.5% or less). For example, it has been reported that the average content uniformity of delivering a 5.0 mL volume of a 1.5% suspension formulation could vary as much as 47% to 108%. See, A. Santoven, E, Sanchez-Negrin, L Charola, M. Llabres, J. G. Farina, “Study of Quality and Stability of Ursodeoxyvholic Acid Formulations for Oral Pediatric Administration, International Journal of Pharmaceutics 477 (2014) 32-38.
Attention is also directed to PCT/US2010/041665 entitled “Material And Process For Incorporation of Low Dosage Active Pharmaceutical Ingredients And Use Thereof.” Disclosed therein is low dose API pharmaceutical tablet formed by spray coating a support excipient with the API. The resulting composition is described as being suitable for direct compression tablet formulation without the need for an additional granulation step to uniformly coat the API onto the support excipient. The support excipient comprises microcrystalline cellulose, a binder and a disintegrant, and is formed by spraying a homogenous slurry of the support excipient components.
Accordingly, the present disclosure is directed at a new method to ensure delivery with acceptable content uniformity for a drug suspension formulation containing a relatively low dose API and relatively high dose API, or a drug suspension formulation containing an API with an excipient.